PROJECT SUMMARY Sepsis is a life-threatening syndrome that involves a systemic inflammatory response that is initiated by an infection. There are an estimated 1.5 million of cases annually in the US with 250,000 resulting in death. The number of cases and associated deaths is expected to increase given the rising at-risk population of elderly individuals and the compounding challenge of antibiotic resistance. Treatment of sepsis involves antimicrobial therapy in addition to several supportive care measures to address the complications of the systemic inflammatory response. In order to effectively and appropriately address the pathophysiological aspects of sepsis, a treatment must provide antimicrobial activity in addition to immunomodulatory properties. It is imperative that efforts to identify new and effective treatment strategies for sepsis shift from the traditional antibiotic development programs that focus solely on antimicrobial activity and turn toward strategies that address both antimicrobial and immunomodulatory aspects of the disease. Arrevus is developing a novel approach to addressing sepsis using Designer Proline-rich Antimicrobial peptide Chaperone protein inhibitors (DPCs), derived from insects and selectively modified, acting as inhibitors to one of the critical bacterial proteins responsible for bacterial protein folding, DnaK. As an adjuvant therapy to current antibiotics, DPCs have the potential to provide a much-improved treatment option for multi-drug resistant (MDR) bacterial infections. Preliminary studies have displayed the potential of ARV-1502, the lead DPC, as an effective antimicrobial agent against MDR bacterial pathogens in addition to providing immunomodulatory effects. Specifically, our efforts have shown that: 1) DPCs show efficacy against MDR pathogens (both gram-negative and gram-positive) alone and in combination with traditional antibiotics; 2) DPCs offer a novel and specific bacterial target; 3) ARV-1502 has demonstrated immunomodulatory properties; and 4) ARV-1502 exhibits a favorable safety profile. Collectively, these data support the continued development of ARV-1502 through an STTR Phase I program targeting proof-of-concept data for the use of ARV-1502 in the treatment of sepsis. In this Phase I proposal, we will build upon significant preliminary data to demonstrate proof-of-concept for the use of ARV-1502 for treating sepsis through two aims. In Aim 1, we will characterize the effect of ARV- 1502 treatment on host innate and adaptive immunity using peripheral blood monocytes and T-cells from sepsis patients. In Aim 2, we will assess the in vivo efficacy of ARV-1502 in murine sepsis models to improve survival (in aim 2A using a near-lethal sepsis model) and host protective immunity (in aim 2B using a survivable murine sepsis model in which animals survive the initial infection but are immunosuppressed). The overall goal of this Phase I program is to generate initial proof-of-concept data and to assess when and how ARV-1502 would be best utilized in sepsis.